Serotonin (5-HT) is a monoamine neurotransmitter and exerts various physiological actions via 5-HT receptors. The 5-HT receptors are classified into 7 families of from 5-HT1 to 5-HT7. Particularly, three subtypes, 5-HT2A, 5-HT2B, and 5-HT2C, are known for 5-HT2 receptor (Non-patent Reference 1).
Irritable bowel syndrome (IBS) is a disease in which abdominal pain or abdominal unpleasantness continues for a long period of time. Based on the symptoms, IBS is classified into a diarrhea-predominant-type, a constipation-predominant-type and a diarrhea-constipation alternating-type. In each case, it has been pointed out that there is a causal relation between morbid state and amount of 5-HT in blood. For example, there is a report pointing out that increase of blood 5-HT concentration after meal occurs in patients of diarrhea-predominant IBS and this deeply relates to the morbid state (Non-patent Reference 2).
Currently, a 5-HT receptor antagonist or a 5-HT receptor agonist is already used in Europe and U.S.A. as an agent for treating IBS, though it is at a clinical trial stage in Japan. Alosetron (5-HT3 receptor antagonist) is used in the clinical field as an agent for treating diarrhea-predominant-type, but side effects such as ischemic colitis, constipation and the like have been reported. In addition, tegaserod (5-HT4 receptor agonist) is used in the clinical field in Europe and U.S.A. as an agent for treating constipation-predominant-type, but its side effects have also been reported (Non-patent References 3 and 4).
In recent years, pharmacological studies on other 5-HT receptor subtypes have also been in progress (Non-patent Reference 5). Regarding the 5-HT2B receptor and 5-HT7 receptor, there are reports pointing out about said receptors and roles in the digestive tracts. For example, there are reports stating that the 5-HT2B receptor is localized in human ileum longitudinal muscle and a 5-HT2B receptor antagonistic compound suppresses contraction by 5-HT (Non-patent Reference 6) and that the 5-HT2B receptor localizing in human colon relates to the 5-HT-induced contraction at the time of electric stimulation and a 5-HT2B receptor antagonistic compound suppresses it (Non-patent Reference 7).
In addition, there are reports stating that the 5-HT7 receptor is present in guinea pig small intestines (Non-patent Reference 8) and rat intestines (Non-patent Reference 9) and concerned in the peristalsis of guinea pig ileum (Non-patent Reference 10). Based on the above, it is expected that a compound having antagonism to 5-HT2B and 5-HT7 receptors is useful as an agent for treating IBS.
On the other hand, migraine is a pulsating headache which is a disease in which a strong pain occurs in one side or both sides of the head and continues for several hours to about 3 days. It is suggested that morbid state of migraine progresses by the following onset mechanism. That is, dura mater blood vessel once contracts by the action of neurotransmitters (e.g., 5-HT and the like) and then dilates again and, at this time, releases vasoactive peptides (e.g., calcitonin gene-related peptide (CGRP) and the like) and serum protein to accelerate inflammation which leads to the onset of headache.
The pharmaceutical targeted at migraine is divided into a preventive agent and a treating agent. The former aims at reducing attack frequency by preventively administering it continuously before onset of the disease and the latter aims at suppressing the pain by taking it after expression of the attack. As the preventive agent for migraine, Ca antagonists (e.g., lomerizine, flunarizine and the like), 5-HT antagonists (e.g., pizotifen, methysergide and the like), β-adrenergic blocking agents (e.g., propranolol and the like), and the like are clinically used in certain countries, but many side effects have been reported on them and sufficient clinical effects have not been obtained.
Regarding the pizotifen as a 5-HT antagonist among the preventive agents described in the above, its efficacy is high in comparison with other agents, but there is a problem in that fatigued feeling, drowsiness, dizziness, weight gain and the side effects are observed at its effective dose (Non-patent Reference 11). It is known that said compound has affinity for all of the 5-HT receptor subtypes and also has high affinity for various receptors such as α1 adrenaline receptor (α1), muscarine 1 receptor (M1), dopamine 2 receptor (D2) and the like.
In recent years, pharmacological studies on 5-HT receptor subtypes have been conducted. It has been reported that a 5-HT2B receptor antagonist suppresses guinea pig m-chlorophenylpiperazine (mCPP)-induced dura mater extravascular protein leakage (Non-patent Reference 12) and that the 5-HT2B receptor localizing on the vascular smooth muscle induces release of nitrogen monoxide (NO) and the NO accelerates release of neuro-peptides such as CGRP, substance P and the like from the trigeminal nerve (Non-patent References 13 and 14). Also, a result which suggests a migraine preventive action has been obtained by an animal model using a 5-HT2B receptor selective antagonist (Non-patent Reference 15). Also, there are reports stating that 5-HT7 receptor is present in the trigeminal nerve (Non-patent Reference 16), concerned in the vasodilation by 5-HT in cerebrovascular smooth muscle (Non-patent Reference 17) or concerned in the dura mater extravascular protein leakage acceleration action (Non-patent Reference 18). In addition, it has been reported in Patent References 1 and 2, applied by the instant applicant and published after the priority date of this application, that a selective 5-HT2B and 5-HT7 receptor dual antagonist is effective for preventing migraine. Based on the above, it is expected that a compound which has the antagonistic activity for 5-HT2B and 5-HT7 receptors and is selective against other receptors is useful as an agent for preventing migraine with less side effects.
As the compound having antagonistic activity for 5-HT2B and 5-HT7 receptors, the compounds shown in Patent References 1 and 2 have been reported.
It has been reported in Patent References 1 and 2, applied by the instant applicant and published after the priority date of this application, that a fluorene compound represented by the following formula (A) has antagonistic activity for 5-HT2B and 5-HT7 receptors and is effective for preventing migraine.

As acylguanidine derivatives having a tricyclic structure, Patent References 3 and 4 are known.
Patent Reference 3 describes that the compounds represented by the following formula (B) is effective for the treatment of central diseases. However, in these compounds, a ring group is linked to the guanidine moiety via a linker X.

(In the formula, R is a cycloalkyl, an aryl, a mono- to tricyclic heteroaryl or the like, R1 and R2 are independently H, an alkyl, alkenyl or the like, X is a bond, an alkene, an alkenylene or the like, and R3 is a cycloalkyl, an aryl, an alkylaryl or the like. See said publication for details.)
In Patent Reference 4, it is reported that the compounds represented by the following formula (C) have an NO synthase inhibitory activity and/or an active oxygen species scavenging activity. However, there is no illustrative disclosure in this publication on a compound in which Φ is a bond or a compound which has —NH2 as —NR13R14.

(In the formula, Φ is a bond or phenylene group, B is —CH2—NO2, an alkyl group, an aryl group or NR13R14 or the like, wherein R13 and R14 are independently hydrogen atom, an alkyl group, cyano group or the like, X is a bond, —O—, —S— or CO— or the like, Y is a bond, —(CH2)m or the like, W is not present, or a bond, S atom or NR15, and R1 to R5 are hydrogen, a halogen or the like. See said publication for details.)    Non-patent Reference 1: Pharmacological Reviews, (USA), 1994, vol. 46, p. 157-203    Non-patent Reference 2: Gut, (England), 1998, vol. 42, p. 42-46    Non-patent Reference 3: The American Journal of Gastroenterology, (USA), 2000, vol. 95, p. 2698-2709    Non-patent Reference 4: The American Journal of Gastroenterology, (USA), 2003, vol. 98, p. 750-758    Non-patent Reference 5: Drugs, (New Zealand), 2001, vol. 61, no. 3, p. 317-332    Non-patent Reference 6: Brutish Journal of Pharmacology, (England), 1995, vol. 114, p. 1525-1527    Non-patent Reference 7: Brutish Journal of Pharmacology, (England), 2002, vol. 135, p. 1144-1151    Non-patent Reference 8: European Journal of Pharmacology, (Holland), 1995, vol. 280, p. 243-250    Non-patent Reference 9: Life Science, (Holland), 2001, vol. 69, p. 2467-2475    Non-patent Reference 10: Brutish Journal of Pharmacology, (England), 2003, vol. 138, p. 1210-1214    Non-patent Reference 11: Journal of Neurology, (Germany), 1991, vol. 238, p. S45-S52    Non-patent Reference 12: Cephalalgia, (England), 2003, vol. 23, p. 117-123    Non-patent Reference 13: The Journal of Biological Chemistry, (USA), 2000, vol. 275, p. 9324-9331    Non-patent Reference 14: Circulation Research, (USA), 1992, vol. 70, p. 1313-1319    Non-patent Reference 15: “Cluster Headache and Related Conditions”, edited by D. W. Bonhaus, vol. 9, (England), Oxford University Press, 1999, p. 278-286    Non-patent Reference 16: Neuroscience Letters, (Holland), 2001, vol. 302, p. 9-12    Non-patent Reference 17: European Journal of Pharmacology, (Holland), 2002, vol. 439, p. 1-11    Non-patent Reference 18: Regional Anesthesia, (England), 1996, vol. 21, p. 219-225    Patent Reference 1: International Publication No. 2005/79845    Patent Reference 2: International Publication No. 2005/80322    Patent Reference 3: International Publication No. 99/20599    Patent Reference 4: International Publication No. 00/17191